Long-acting preparations containing pharmacologically active substances, in particular peptide drugs, are used to maintain the body fluid concentration of each peptide within a certain effective concentration range over a prolonged period of time. Such substances include, according to the mechanisms of manifestation of their pharmacological effects,
a) pharmacologically active substances whose pharmacological effects do not much depend on their effective body fluid concentrations and will not be harmful to living bodies even when manifested excessively, and PA1 b) pharmacologically active substances whose pharmacological effects depend on their effective body fluid concentrations and may be harmful to living bodies when manifested abruptly or excessively, so that dose adjustment is required at regular intervals.
Japanese Patent Application Laid-open No. 213/1990 discloses a technology of long-acting preparations of physiologically active peptides which contain hyaluronic acid and nontoxic salts thereof. In an example, a long-acting calcitonin or elcatonin preparation containing sodium hyaluronate in a concentration of 5% was subcutaneously administered to male rats. Reduction in blood calcium level lasted at least 12 hours. Similarly, when a long-acting human growth hormone preparation containing sodium hyaluronate in a concentration of 5% was administered to male rats, a blood human growth hormone concentration was found lasting at least 12 hours. With these preparations, an obvious prolongation of the residence in blood was observed as compared with a comparative example in which sodium hyaluronate was not used. However, in another comparative example in which a tegafur preparation containing sodium hyaluronate in a concentration of 5% was subcutaneously administered to male rats, no prolonging effect was observed.
These inventions utilize the retarded diffusion, at the site of administration, of a substance in solution as caused by the viscosity of hyaluronic acid. However, cationic group-containing substances may undergo ion exchange with carboxyl-containing hyaluronic acid macromolecules and this exchange can further retard the diffusion of said substances. Japanese Patent Application Laid-open No. 213/1990 mentions 3 to 7% as the most preferred concentration of hyaluronic acid itself. However, because of its high viscosity, bubbles may be formed and, if formed, pose a great problem, namely, centrifugation or deaeration under reduced pressure is required for the elimination thereof. At the same time, its high viscosity makes it necessary to use a large-gauge injection needle, and the pain possibly caused thereby cannot be ignored.
Japanese Patent Application Laid-open No. 287041/1989 describes an example in which hyaluronic acid is used in a concentration of 1%. The "caution in use" for a preparation sold on the mark, an intraarticular injection containing sodium hyaluronate in the same concentration of 1%, recommends the use of a fairly large-gauge needle of about 18-20 G. Such preparation, as an injection for subcutaneous administration, can cause great pain in patients.
Furthermore, Japanese Patent Application Laid-open No. 129226/1987 describes that the hyaluronic acid concentration in injectable products may range from about 0.05% to 4% (by weight) and may be higher depending on the final use of the products, without mentioning on any particular application to injections. At any rate, it is readily presumable by analogy that a retention prolonging effect on pharmacologically active substances cannot be obtained without using hyaluronic acid in a relatively high concentration, as mentioned above. There is a possibility that sustained release of pharmacologically active substances may be attained depending on the viscosity of a high concentration of hyaluronic acid. There is also a possibility that sustained release of pharmacologically active substances may be accomplished using the fact that the viscosity of hyaluronic acid can be increased by reducing the pH into the acid side (e.g. to about 2.5). However, a higher hyaluronic acid viscosity means a greater difficulty in the administration as an injection. In addition, there is a fear that a deviation of the pH of the hyaluronic acid solution from the physiological pH range may affect the stability of the pharmacologically active substances and/or cause damages to living body tissues at the site of administration.
In EP312208, it is disclosed that the combination of glycosaminoglycans such as hyaluronic acid, chondroitin, chondroitin-6-sulfate, chondroitin-4-sulfate, keratan sulfate, heparan sulfate, heparin and mitogenic or angiogenic polypeptide, growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF), fibroblast growth factor (FGF), insulin like growth factor (IGF), platelet derived growth factor (PDGF) provides a good aqueous gel formulation for wound healing. But, there is no working example of the combination of glycosaminoglycan except hyaluronic acid and the polypeptide growth factors.
In WO91/00739, the technique to stabilize motilin by combining the peptide with heparin is described.
As mentioned above, several problems remain to be solved as regards the adaptability and compatibility in the administration to living bodies although attempts have been made to use hyaluronic acid in producing sustained release preparations of pharmacologically active substances.